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IEM Biotechnology Symposium 1
Cells as Devices: Engineering the Genome

Wednesday, April 17, 10:30-12:00
Meridian Ballrooms 1, Graduate Minneapolis

Organizer: David Largaespada, University of Minnesota

"Cells as Devices: Engineering the Genome"
Perry Hackett, Professor, Center for Genome Engineering, University of Minnesota

"Semi-synthesis of a Neuroprotective Natural Product of Unknown Origin"
Michael Smanski, Assistant Professor, University of Minnesota

"Using Genome Engineering to Create Biomedical Swine Models"
Adrienne Watson, Senior Director, Preclinical Research, Recombinetics

"Transposons and Targeted Nucleases for Cancer Gene and Pathway Discovery"
David Largaespada, University of Minnesota


Session Abstract:

This symposium will highlight emerging areas of science and technology development at the interface of biology with engineering to deliver improved healthcare. The full day symposium is comprised of three sessions that engage with scientific and thought leaders at the University of Minnesota, the Mayo Clinic and local biotech industry. The topics of the sessions are genome engineering, cancer bioengineering, and Alzheimer's disease and aging. We intend to develop a pre-eminent annual meeting for cutting-edge medical science and technology, one that embraces the full spectrum of biomedical applications and technological approaches to include molecular, genetic, and cell-based therapeutic strategies. 


Session Organizer Bios:

David Largaespada, University of Minnesota
Dr. Largaespada is an authority on mouse genetics, gene modification, cancer genes, and disease models. His lab specializes in cancer functional genomics using in vivo transposon mutagenesis and targeted nucleases. Current projects are focused on sarcomas, brain tumors, hepatocellular carcinoma, and Neurofibromatosis Type 1 syndrome. He is currently a Full Professor in the Department of Pediatrics and the Department of Genetics, Cell Biology and Development at the University of Minnesota. He is the Associate Director for Basic Research in the Masonic Cancer Center at University of Minnesota. Dr. Largaespada currently holds the Hedberg Family/Children’s Cancer Research Fund Endowed Chair in Brain Tumor Research. Dr. Largaespada was awarded the University of Minnesota McKnight Land-Grant Professorship in 2000 and the American Cancer Society Research Professor Award in 2013. He has published over 175 scientific articles, many in high impact journals such as Science, Nature and Nature Genetics. Dr. Largaespada has co-founded three biotechnology companies.


Speaker Bios:

Perry Hackett, University of Minnesota

Perry Hackett, Professor, Center for Genome Engineering, University of Minnesota
Perry Hackett (BS, Physics/Stanford; Ph.D., Biophysics and Genetics/U Colorado; postdoc at the Max Planck Institute for Cell Biology and UCSF) came to UMN Dept, of Genetics, Cell Biology and Development in 1980. He has co-founded the Center for Genome Engineering and three biotech companies based on his research in genome engineering of vertebrate animals and human gene therapy.

 

 

Michael Smanski, Assistant Professor, University of Minnesota
Michael Smanski is an Assistant Professor in the Department of Biochemistry, Molecular Biology, and Biophysics and the Biotechnology Institute. He research group seeks to leverage new DNA synthesis and assembly technologies to engineering multi-gene systems with applications in medicine, public health, agriculture, and the environment.

Adrienne Watson, Senior Director, Preclinical Research, Recombinetics
Dr. Watson completed her Ph.D. and postdoctoral studies at the University of Minnesota, generating mouse models of Neurofibromatosis Type 1 (NF1) and NF1-related malignancies, elucidating novel genetic pathways, and targeted cancer therapy candidates. In 2013, she joined Recombinetics, which uses gene-editing technology to create large animal models of human disease.


Presentation Abstracts:

"Cells as Devices: Engineering the Genome"
Medical devices in the late 20th century flourished based on the rise of integrated circuits, a principal component of medical metal-packaged products. The 21st century will be marked by breakthroughs in genetic circuit design that will enable cellular engineering at levels from individual cellular devices, to whole organs, to whole animals engineered to facilitate invention and testing of advanced classical (metal-based) devices. Exciting research in these areas is happening at the University of Minnesota in collaboration with biotech companies.

"Semi-synthesis of a Neuroprotective Natural Product of Unknown Origin"
Serofendic acid is a potent neuroprotective natural product originally isolated from fetal calf serum. Its ent-atisane carbon scaffold suggests that it is not of mammalian origin, but the biosynthetic source is not known. Here I present our efforts to create a sustainable and robust production pipeline by creating a synthetic metabolic gene cluster in the industrial bacterium, Streptomyces albidoflavus. We leverage this platform to investigate the bioactivity, mechanism of action, and structure-activity-relationship of this promising compound.

"Using Genome Engineering to Create Biomedical Swine Models"
Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of disease are valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Dr. Watson will describe this new approach to disease modeling with a focus on the use of genome-edited swine for cancer research.

"Transposons and Targeted Nucleases for Cancer Gene and Pathway Discovery"
We developed Sleeping Beauty (SB) transposon-based insertional mutagenesis models of cancer in mice. Tissue-specific mobilization of SB transposons (T2/Onc) causes stochastic activation of endogenous proto-oncogenes and inactivation of tumor suppressor genes resulting in acceleration of tumor development. Since our initial reports in 2005, over 50 papers have been published describing SB or PiggyBac (PB) based cancer screens in mice. Cancers derived from all three germ layers including carcinomas, sarcomas, neuroectodermal tumors, and hematopoietic malignancies have been produced. Screens for cancer cell drug resistance and metastasis have been performed. Because T2/Onc transposons are designed to create fusions with endogenous gene transcripts, deep RNA sequencing of tumors induced by transposon mutagenesis reveals the genes targeted in the major tumor clone. In turn, correlations can be drawn between the alteration of specific genes and changes in tumor gene expression patterns. Thus, the goals of our recent research have been to discover novel associations between SB-induced tumor phenotypes and specific driver gene alterations (i.e. the tumor genotype). RNA and DNA sequencing has defined common insertion sites of the SB transposon, allowing for detection of the most frequently mutated driver genes. Moreover, RNA sequencing has revealed tumor molecular subtypes, in many cases with correlating T2/Onc-induced insertion mutations. Several examples will be described: mammary tumors, osteosarcoma, medulloblastoma and central nervous system primitive neuro-ectodermal tumors. In each case, RNA sequencing has revealed novel genotype-phenotype correlations including drivers of high cell cycle activity, metastasis, white blood cell exclusion from the tumor, SHH pathway activation, and hormone receptor signaling. These models provide a source of genetically heterogenous tumors with the same initiating mutation useful for identifying cooperating pathways and drivers of specific tumor phenotypes. Targeted nucleases are then used to validate cancer genes and pathways in human cell models. We’ve also used the CRISPR/Cas9 system for performing genome wide screens for tumor suppressor genes in human cells. A final use of the CRISPR/Cas9 system is genome wide synthetic lethality screens for loss of specific tumor suppressor genes and an example of a screen on an NF1 deficient background will be described.


Related Sessions:

IEM Biotechnology Symposium 2
IEM Biotechnology Symposium 3

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